Overview of Charcot‐Marie‐Tooth Disease Type 1A

Abstract

Type 1A CMT disease is most commonly due to a segmental duplication on chromosome 17p11.2, leading to the presence of an extra copy of the gene for peripheral myelin protein 22 (PMP22). Inheritance is autosomal dominant in pattern. Analysis of nerve biopsies suggests that the disorder is caused by increased gene dosage. Occasionally CMTIA results from point mutations in the PMP22 gene. Onset of symptoms in cases with a duplication is usually in the first decade of life; slowing of nerve conduction velocity is evident from the age of 2 years. Active demyelination is restricted to childhood. It leads to hypertrophic "onion bulb" changes and is accompanied and followed by progressive axonal loss. The commonest clinical phenotype is the CMT syndrome with distal muscle wasting and weakness, tendon areflexia, usually mild sensory loss, and foot deformity. Other phenotypes include the Roussy-Lévy syndrome, in which postural tremor and ataxia are associated, and cases with severe distal sensory loss and acrodystrophic changes.

Pediatric Charcot-Marie-Tooth Disease

“…The weakness makes voluntary toe walking difficult unless heel cord contracture is present. 56 The most typical foot abnormalities are high arch (pes cavus) and hammer toes (claw feet), but less frequently flat foot is present (Fig. 1).…”

The ER Glycoprotein Quality Control System

“…Thyroid peroxidase deficiency (de Carvalho et al, 1994; Thyroid peroxidase + CNX/CRT Kim and Arvan, 1995;Fayadat et al, 2000) Thyroxin-binding globulin deficiency ¶ Thyroxin-binding globulin + (Miura et al, 1994;Refetoff et al, 1996) Osteogenesis imperfecta (Lamande and Bateman, 1999) Type I procollagen + Hereditary hypofibrinogenemia (Roy et al, 1996) Fibrinogen + CNX α1-Antichymotrypsin (ACT) deficiency (Callea et al, 1992) α1-Antichymotrypsin + CNX Neurophyseal diabetes insipidus (Morello et al, 2001) Vasopressin precursor protein + CNX, Prolonged Assoc. Nephrogenic diabetes insipidus (Tamarappoo et al, 1999) Aquaporin II -Charcot-Marie-Tooth disease (Thomas, 1999;Mendell, 1998) Peripheral myelin protein 22 + CNX Pelizaeus-Merzbacher disease (Yool et al, 2000;Swanton et al, 2003) Proteolipoprotein -CNX, Prolonged Assoc. Alzheimer disease (Shastry, 2001) Presenilin + CNX Straussler-Scheinker syndrome (Rudd et al, 2001b; Prion protein processing defect + CNX Collins et al, 2001) Hereditary Creutzfeldt-Jacob disease (Rudd et al, 2001b; Prion protein processing defect + CNX Collins et al, 2001) von Willebrand Disease von Willebrand factor (VWF) + Type IIA (Englender et al, 1996;Lyons et al, 1992) VWF Types I and III (Allen et al, 2001) Types I and III associated VWF variant CNX/CRT, CNX Prolonged Assoc.…”

Phenotype Variant of the Common Duplication at 17p11.2

“…An argument against phentermine is the fact that blurred vision occurred not earlier than 2 months after initiation of the drug and that it persisted despite discontinuation of the drug. An argument for a causal relation between the mutation and the phenotype is that single features of this phenotype had been reported earlier [1,2,[9][10][11][12] . It cannot be excluded, however, that the described patient The presented case shows that the duplication 17p11.2 may be associated with tremor, sensorineural hearing loss, unilateral papilledema, hypothyroidism, short stature in addition to the classical manifestations distal weakness of all four limbs sensory disturbances in the upper and lower limbs, and foot deformity.…”

“…Tremor has been rarely described together with HMSN1 [4] but is a frequent feature of Roussy-Levy syndrome [1] . Hearing loss has been rarely reported in association with a duplication at 17p11.2 [2] but has been more frequently found together with point mutations in the PMP22 gene [2,[5][6][7][8] .…”

“…The autosomal-dominantly inherited 1.5-Mb tandem duplication in the PMP22 gene at 17p11.2 usually manifests as hereditary sensorimotor polyneuropathy with foot deformity (HMSNIA) [1,2] . In single cases, however, it has been found in association with additional features, such as sensorineural hearing loss, moderate developmental delay, gait disturbance, autism-related disorder, mild dysmorphic features, or growth factor deficiency [3] .…”